首页|Therapeutic Targeting of PKM2 Ameliorates NASH Fibrosis Progression in a Macrophage-Specific and Liver-Specific Manner

Therapeutic Targeting of PKM2 Ameliorates NASH Fibrosis Progression in a Macrophage-Specific and Liver-Specific Manner

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Nonalcoholic steatohepatitis(NASH)may soon become the leading cause of end-stage liver disease world-wide with limited treatment options.Liver fibrosis,which is driven by chronic inflammation and hepatic stellate cell(HSC)activation,critically determines morbidity and mortality in patients with NASH.Pyruvate kinase M2(PKM2)is involved in immune activation and inflammatory liver diseases;however,its role and therapeutic potential in NASH-related fibrosis remain largely unexplored.Bioinformatics screening and analysis of human and murine NASH livers indicated that PKM2 was upregulated in non-parenchymal cells(NPCs),especially macrophages,in the livers of patients with fibrotic NASH.Macrophage-specific PKM2 knockout(PKM2FL/FLLysM-Cre)significantly ameliorated hepatic inflammation and fibrosis severity in three distinct NASH models induced by a methionine-and choline-deficient(MCD)diet,a high-fat high-cholesterol(HFHC)diet,and a western diet plus weekly carbon tetrachloride injection(WD/CCl4).Single-cell transcriptomic analysis indicated that deletion of PKM2 in macrophages reduced profibrotic Ly6Chigh macrophage infiltration.Mechanistically,PKM2-dependent glycolysis pro-moted NLR family pyrin domain containing 3(NLRP3)activation in proinflammatory macrophages,which induced HSC activation and fibrogenesis.A pharmacological PKM2 agonist efficiently attenuated the profi-brotic crosstalk between macrophages and HSCs in vitro and in vivo.Translationally,ablation of PKM2 in NPCs by cholesterol-conjugated heteroduplex oligonucleotides,a novel oligonucleotide drug that preferen-tially accumulates in the liver,dose-dependently reversed NASH-related fibrosis without causing observ-able hepatotoxicity.The present study highlights the pivotal role of macrophage PKM2 in advancing NASH fibrogenesis.Thus,therapeutic modulation of PKM2 in a macrophage-specific or liver-specific manner may serve as a novel strategy to combat NASH-related fibrosis.

Pyruvate kinase M2MacrophagesNonparenchymal cellsHeteroduplex oligonucleotideNonalcoholic steatohepatitisLiver fibrosis

Hengdong Qu、Di Zhang、Junli Liu、Jieping Deng、Ruoyan Xie、Keke Zhang、Hongmei Li、Ping Tao、Genshu Wang、Jian Sun、Oscar Junhong Luo、Chen Qu、Wencai Ye、Jian Hong

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State Key Laboratory of Bioactive Molecules and Druggability Assessment,Jinan University,Guangzhou 510632,China

Department of Pathophysiology,School of Medicine,Jinan University,Guangzhou 510632,China

Department of Microbiology and Immunology,School of Medicine,Jinan University,Guangzhou 510632,China

Department of Liver Transplantation,Guangdong Provincial Hospital of Traditional Chinese Medicine,Guangzhou 510630,China

Department of Hepatobiliary and Pancreatic Surgery,The First Affiliated Hospital of Jinan University,Guangzhou 510630,China

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Key-Area Research and Development Program of Guangdong ProvinceLocal Innovative and Research Teams Project of Guangdong Pearl River Talents ProgramGuangdong Major Project of Basic and Applied Basic ResearchNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaGuangdong Basic and Applied Research FoundationGuangdong Basic and Applied Research Foundation

2020B11111100042017BT01Y0362023B0303000004818719878229368082293681822731542023A15150129052022A1515012581

2024

10.1016/j.eng.2024.05.005

工程(英文)

工程(英文)

CSTPCDEI
ISSN：2095-8099
年,卷(期)：2024.41(10)